Arachidonic acid is a key biological intermediate that is converted to a large number of eicosanoids with potent biological activities. Metabolism of arachidonic acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of leukotrienes such as LTB4, LTC4 and LTD4, and 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE). 5-HETE is oxidized to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) by the action of 5-hydroxyeicosanoid dehydrogenase, a microsomal enzyme found in leukocytes and platelets, as well as endothelial and epithelial cells.
5-Oxo-ETE is a potent chemoattractant for eosinophils and neutrophils, and elicits a variety of rapid responses in these cells. Examples of the responses in these cells in addition to cell migration and tissue infiltration include actin polymerization, calcium mobilization, integrin expression, shedding of L-selectin, degranulation, and superoxide production. The primary target of 5-oxo-ETE is most likely the eosinophil, and among lipid mediators it is the strongest chemoattractant for these cells. It has been shown to induce transendothelial migration of eosinophils and to induce the infiltration of both eosinophils and neutrophils into the skin. 5-Oxo-ETE also promotes the survival of eosinophils and possibly other types of inflammatory cells through, for example, the induction of GM-CSF release from monocytes. 5-Oxo-ETE is also a chemoattractant for monocytes and has been shown to stimulate the proliferation of prostate tumor cells.
The biological effects of 5-oxo-ETE are mediated by a G, protein-coupled receptor termed the OXE receptor. This receptor is expressed on eosinophils, neutrophils, and monocytes, as well as on prostate tumor cells.
Eicosanoids produced by the 5-LO pathway are known to be important mediators for inflammatory and allergic diseases such as asthma, allergic rhinitis, chronic obstructive pulmonary disorder, atopic dermatitis and acne, and have been shown to play a role in certain cancers such as prostate cancer. The biological effects of 5-oxo-ETE suggest that agents which block its action may function as therapeutic or prophylactic agents for such diseases. It would be desirable therefore to be provided with antagonists of the 5-oxo-ETE receptors, such as the OXE receptor.